title: Merkel cell polyomavirus small T antigen targets the NEMO adaptor protein to disrupt inflammatory signaling.
abstract: Merkel cell carcinoma (MCC) is a highly aggressive nonmelanoma skin cancer arising from epidermal mechanoreceptor Merkel cells. In 2008, a novel human polyomavirus, Merkel cell polyomavirus (MCPyV), was identified and is strongly implicated in MCC pathogenesis. Currently, little is known regarding the virus-host cell interactions which support virus replication and virus-induced mechanisms in cellular transformation and metastasis. Here we identify a new function of MCPyV small T antigen (ST) as an inhibitor of NF-κB-mediated transcription. This effect is due to an interaction between MCPyV ST and the NF-κB essential modulator (NEMO) adaptor protein. MCPyV ST expression inhibits IκB kinase α (IKKα)/IKKβ-mediated IκB phosphorylation, which limits translocation of the NF-κB heterodimer to the nucleus. Regulation of this process involves a previously undescribed interaction between MCPyV ST and the cellular phosphatase subunits, protein phosphatase 4C (PP4C) and/or protein phosphatase 2A (PP2A) Aβ, but not PP2A Aα. Together, these results highlight a novel function of MCPyV ST to subvert the innate immune response, allowing establishment of early or persistent infection within the host cell.
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffiths
authors.forename: Hussein
authors.initials: H
authors.lastname: Abdul-Sada
authors.forename: Laura M
authors.initials: LM
authors.lastname: Knight
authors.forename: Brian R
authors.initials: BR
authors.lastname: Jackson
authors.forename: Kathryn
authors.initials: K
authors.lastname: Richards
authors.forename: Emma L
authors.initials: EL
authors.lastname: Prescott
authors.forename: A Howard S
authors.initials: AH
authors.lastname: Peach
authors.forename: G Eric
authors.initials: GE
authors.lastname: Blair
authors.forename: Andrew
authors.initials: A
authors.lastname: Macdonald
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitehouse
mesh_terms: D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate; D059965:Merkel cell polyomavirus / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D027601:Polyomavirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D011485:Protein Binding; D014412:Tumor Virus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology
chemical_list: D000957:Antigens, Viral, Tumor; C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase